1. Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects.
- Author
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Migoya EM, Bergman A, Hreniuk D, Matthews N, Yi B, Roadcap B, Valesky R, Liu L, Riffel K, Groff M, Zhao JJ, Musson DG, Gambale J, Kosoglou T, Statkevich P, Lasseter KC, Laurent A, Johnson-Levonas AO, Murphy G, Gottesdiener K, and Paolini JF
- Subjects
- Adolescent, Adult, Analysis of Variance, Anticholesteremic Agents administration & dosage, Anticholesteremic Agents adverse effects, Area Under Curve, Azetidines administration & dosage, Azetidines adverse effects, Cross-Over Studies, Drug Combinations, Drug Therapy, Combination, Ezetimibe, Female, Humans, Male, Middle Aged, Reference Values, Simvastatin administration & dosage, Simvastatin adverse effects, Tablets, Therapeutic Equivalency, Time Factors, Treatment Outcome, Anticholesteremic Agents pharmacokinetics, Azetidines pharmacokinetics, Simvastatin pharmacokinetics
- Abstract
Objective: To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA)., Methods: In this open-label, randomized, 2-part, 2-period crossover study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within prespecified bounds of (0.80, 1.25)., Results: The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/ SIMVA and EZE + SIMVA were generally well tolerated., Conclusions: The lowest and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dosages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tablet across the clinical dose range.
- Published
- 2006
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